Difference between the resistance mechanisms of aclacinomycin- and adriamycin-resistant P388 cell lines.

Abstract

Aclacinomycin (ACR) is an anthracycline anticancer drug that shows marked effects in Adriamycin (ADM)-resistant tumors. ADM, however, is not effective against ACR-resistant tumor cells. When tumor cells acquire resistance to ACR, though the resistance is not easily acquired, they show strong cross-resistance to ADM. To study the mechanism underlying these phenomena, we studied the resistance mechanism of ACR- and ADM-resistant P388 leukemia cells. The P388/ACR cells showed 4.9- and 100-fold resistance to ACR and ADM, respectively, whereas the P388/ADM cells showed respectively 2.0- and 270-fold resistance. Both P388/ACR and P388/ADM cells expressed large amounts of P-glycoprotein, and the amount was 3-fold higher in the P388/ACR than in the P388/ADM cells. As a result, the accumulation of vincristine and ADM were greatly reduced in P388/ACR and P388/ADM cells, as compared with the parental P388 cells. The accumulation of ACR, however, was moderately reduced in both the resistant cell lines. ACR accumulation in P388/ACR and P388/ADM cells was reduced to respectively 37 and 64% of the level in P388 cells. The amount and the activity of topoisomerase II were comparable in P388 and P388/ACR cells, but they were reduced in P388/ADM cells. Consequently, the formation of protein (topoisomerase II)-DNA cross-links induced by a topoisomerase II inhibitor was more prominent in the P388 and P388/ACR nuclei than in the P388/ADM nuclei. Notably, ACR could reduce the protein-DNA cross-links equally in the nuclei of P388, P388/ACR, and P388/ADM cells.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: J Dong, M Naito, T Tatsuta, H Seimiya, O Johdo, T Tsuruo
• Journal: Oncology research (Oncol Res) Vol. 7 Issue 5 Pg. 245-52 ( 1995) ISSN: 0965-0407 [Print] United States
• PMID: 8534930 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antibiotics, Antineoplastic
• DNA, Neoplasm
• aclacinomycins
• Vincristine
• Etoposide
• Aclarubicin
• Doxorubicin
• Verapamil
• DNA Topoisomerases, Type II

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics)
• Aclarubicin (analogs & derivatives, pharmacokinetics, pharmacology)
• Animals
• Antibiotics, Antineoplastic (pharmacokinetics, pharmacology)
• Cell Nucleus (drug effects, metabolism)
• DNA Topoisomerases, Type II (metabolism)
• DNA, Neoplasm (drug effects, metabolism)
• Doxorubicin (pharmacokinetics, pharmacology)
• Drug Resistance, Multiple (genetics)
• Drug Resistance, Neoplasm
• Etoposide (pharmacology)
• Humans
• Immunoblotting
• Leukemia P388
• Tumor Cells, Cultured
• Verapamil (pharmacology)
• Vincristine (pharmacology)